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LIF gene therapy for Multiple Sclerosis
Multiple sclerosis is a debilitating disease of the central nervous system that has yet to be cured. The autoimmune disease is characterized by axonal demyelination, inflammation, and even loss of function (depicted in Figure 1). Inflammation leads to the loss of oligodendrocytes (cells that produce myelin). Particular therapies are needed to repair damaged neurons. Previous therapies have focused on manipulating the activity of periph eral immune cells, but this does not help with ameliorating disease progression (Gresle et al., 2012). One potential therapy that has been implicated in repairing neuronal damage is work with neural progenitor cells (NPCs). Neural Progenitor cells and LIF Neural progenitor cells are good candidates for an MS therapeutic approach in their ability to repair myelin tissue that has been damaged. NPCs can do this through differentiation into oligodendrocytes (Cao et al., 2011). NPCs also produce anti-inflammatory agents in other areas of the central nervous system, including LIF, BDNF, BMP-4, and TNFalpha. Cao et al found leukemia inhibitory factor as the factor that prevents differentiation of Th17 cells. Leukemia inhibitory factor is produced by NPCs, and has been experimentally shown to reduce encephalomyelitis (EAE), also known as neural inflammation (Cao et al., 2011). Brain lesions from MS patients contain T cells and macrophages that have been shown to secrete LIF. LIF binds to a receptor complex with a gp130 subunit and LIFR (Figure 2). Downstream signaling pathways include the JAK/STAT and MAPK pathways, promoting cell survival (Figure 3) . In the healthy nervous system, there are no detectable levels of LIF (Slaets et al., 2010). However, with injury or disease, levels increase in LIF as a neuroprotective response. Studies have shown increases of the cytokine in response to spinal cord injury. Neuroprotective qualities of LIF are also exhibited in rat ischemic brain injury, where less neurological problems are seen in animals with LIF treatment (Slaets et al., 2010). Research has shown that patients with MS exhibit much higher levels of leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF), which are both cytokines and members of the interleukin-6 family (Gresle et al., 2012). Th17 T-helper cells- therapy targets Data suggest that certain T-helper cells play a role in axonal demyelination, as well as inflammation. These include Th1 cells, which produce interferon, as well as Th17 T-helper cells, which produce interleukin-17. Furthermore, many patients with multiple sclerosis have been shown to have Th17 cells in brain lesion regions. Cerebrospinal fluid and serum samples from these patients have also shown increased levels of interleukin-17 (Cao et al., 2011). Animal models that have genetically lower levels of Th17 cells show no signs of encephalomyelitis. Th17 cells have also been implicated in progression of autoimmune disease. Preliminary studies with mouse models have shown that by intravenously introducing NPCs, Th17 cell differentiation was negatively effected, specifically through leukemia inhibitory factor (Cao et al., 2011). Therapy Progression/ Procedure The research for nerual progenitor cell and leukemia inhibitory factor therapy is still quite new. Levels of leukemia inhibitory factor have been monitored in MS patients, but all experimental studies are being performed in animal models like rats and mice. This therapy has the potential to aid in slowing disease progression of MS, but it is still in a stage of infancy in regards to research. Since clinical trials have not been described in patients yet, a paper will be described that illustrates the ability for LIF to induce neuronal generation, which is critical for MS therapy in the future. LIF treatment has been studied in rats that have undergone ischemic brain injury (Suzuki et al., 2005). Rats were either injected with phosphate-buffered saline or recombinant leukemia inhibitory factor in a region adjacent to the area in the cerebral cortex where the brain injury was induced. Brain sections were taken and analyzed, as shown in Figure 4. In (A), sections were stained with triphenyltetrazolium chloride (TTC). The stain highlights the healthy tissue, but does not stain the infarct area of the brain. The infarct area is reduced in animals that were injected with LIF, as shown in (A). In (B), cresyl violet staining showed greater amounts of damage in PBS-treated rats compared to LIF-treated animals. In (D), a TUNEL assay was conducted on the brain slices. This assay detects nicked DNA that has undergone damage. As shown in Figure 4, there is a greater amount of TUNEL staining in ischemic rats that have undergone PBS-treatment. The results from this article look promising for gene therapy towards damaged neurons. As diagrammed in Figure 3, LIF activates pathways that promote cell survival and proliferation, which may have the potential to be harnessed for MS gene therapy. References Cao W., Yang Y., Wang Z., Liu A., Fang L., Wu F., Hong J., Shi Y., Leung S., Dong C., and Zhang J. Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Immunity 2011 (35) 273-284. Gresle M., Alexandrou E., Wu Q., Egan G., Jokubaitis V., Ayers M., Jonas A., Doherty W., Friedhuber A., Shaw G., Sendtner M., Emery B., Kilpatrick T., and Butzkueven H. Leukemia inhibitory factor protects axons in experimental autoimmune encephalomyelitis via an oligodendrocyte-independent mechanism. PLOS One 2012 (7) 1-12. Slaets H., Hendriks J.A., Kilpatrick T.J., and Hellings N. Therapeutic potential of LIF in multiple sclerosis. Trends in Molecular Medicine 2010 (16) 493-500. Suzuki S., Yamashita T., Tanaka K., Hattori H., Sawamoto K., Okano H., and Suzuki N. Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuate ischemic brain injury in rats. Journal of central blood flow and metabolism 2005 (25) 685-693. Leukemia Inhibitory Factor Wiki